Monday, August 4, 2025 8/4/2025

Role of the microbiota in DNA methylation and CRC development

Award Number: R01CA214005
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2023

Group Awards By:

View Award Description

Role of the microbiota in DNA methylation and CRC development - The colonic microbiome has been implicated in colorectal cancer (CRC) pathogenesis but the exact mechanisms underlying these observations remain incompletely understood. We have observed striking associations between specific host microbes and aberrant DNA methylation in CRC. For example, Fusobacterium species are substantially enriched in cancers affected by the CpG Island Methylator Phenotype (CIMP). Preliminary data based on sequencing and qPCR validation also show enrichment of bacteria that have been linked to disease in humans or mouse models (E.coli sp., Klebsiella sp. etc.). High levels of these pathogenic bacteria are associated with recurrences in CIMP+ colon cancers. This unexpected link between colonic microbiota and epigenetic control was also seen in an analysis of DNA methylation genome wide in the colonic mucosa of germ free (GF) mice compared to conventionalized mice, where we found that reintroduction of bacteria led to hypermethylation of normally unmethylated CpG island sites (the main anomaly seen in CIMP+ cases). Thus, our preliminary data support a new hypothesis, that the GI microbiota affects colonic neoplasia through inducing or modulating aberrant DNA methylation and epigenetic control. Mechanistically, we propose that multiple parallel mechanisms may be contributing to this link including DNA damage associated recruitment of silencing complexes, and metabolic disturbances whereby bacteria secrete metabolites and/or toxins that diffuse into colonic epithelial cells and affect DNA methylation directly (e.g. 2-hydroxyglutarate [2-HG], which inhibits the TET DNA demethylase enzymes) or indirectly (e.g. butyrate, which is known to modulate epigenetics through inhibition of histone deacetylases). To test these hypotheses, we propose three specific aims: (1) Define the microbiome across the spectrum of CIMP+ tumors. We will use 16S RNA genomic sequencing in an extensive tumor (cancer, precursors and adjacent normal) set simultaneously characterized for CIMP, mutations and gene expression. (2) Impact of CIMP+ associated bacteria on tumorigenesis and DNA methylation in mice. GF Il10-/-;Apcmin/+ mice will be colonized with bacterial candidates (e.g. E.coli, F.nucleatum, K.pneumonia) and tumor incidence, severity, survival as well as DNA methylation and gene expression in normal and tumor tissues will be evaluated. We will also test whether drugs targeting DNA methylation are effective in prevention of bacteria-associated tumorigenesis. (3) Study metabolites by which bacteria influence DNA methylation profiles. We will use metabolomics on cultures of bacteria associated with CIMP and on lysates from CIMP+ and CIMP- cancers to identify metabolites that potentially modulate DNA methylation. These (e.g. 2HG, butyrate) will be tested for effects on DNA methylation (in cell culture and in GF mice) and tumorigenesis (in mice). The proposed research tests a new mechanism for microbiome-associated tumorigenesis and has important implications for detection, prevention and treatment of CRCs.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$151,935 )
2024	2022	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Cancer Cause and Prevention Research	000	6	4/10/2024	NON-COMPETING CONTINUATION	-$151,935
														Subtotal = -$151,935

Issue Date FY: 2022 ( Subtotal = $574,730 )
2022	2022	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Cancer Cause and Prevention Research	001	6	4/28/2022	NON-COMPETING CONTINUATION	$46,607
2022	2022	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Cancer Cause and Prevention Research	000	6	11/15/2021	NON-COMPETING CONTINUATION	$524,319
2022	2018	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Cancer Cause and Prevention Research	002	1	9/26/2022	NEW	$3,804
														Subtotal = $574,730

Issue Date FY: 2021 ( Subtotal = $564,123 )
2021	2021	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Cancer Cause and Prevention Research	000	5	12/2/2020	NON-COMPETING CONTINUATION	$535,917
2021	2021	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Cancer Cause and Prevention Research	001	5	1/21/2021	NON-COMPETING CONTINUATION	$28,206
														Subtotal = $564,123

Issue Date FY: 2020 ( Subtotal = $600,157 )
2020	2020	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Cancer Cause and Prevention Research	002	4	1/14/2020	NON-COMPETING CONTINUATION	$60,017
2020	2020	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Cancer Cause and Prevention Research	001	4	11/20/2019	NON-COMPETING CONTINUATION	$540,140
2020	2019	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Cancer Cause and Prevention Research	004	3	6/16/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$75,706
2020	2019	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Cancer Cause and Prevention Research	000	3	11/19/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2018	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Cancer Cause and Prevention Research	003	1	6/16/2020	NEW	-$75,706
														Subtotal = $600,157

Issue Date FY: 2019 ( Subtotal = $602,612 )
2019	2019	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Cancer Cause and Prevention Research	001	3	8/9/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$602,612
2019	2019	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	2	11/23/2018	NON-COMPETING CONTINUATION	$563,820
2019	2019	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Cancer Cause and Prevention Research	002	2	8/26/2019	NON-COMPETING CONTINUATION	-$563,820
														Subtotal = $602,612

Issue Date FY: 2018 ( Subtotal = $567,545 )
2018	2018	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	1	12/15/2017	NEW	$567,545
														Subtotal = $567,545

Grand Total All Awards = $2,757,232

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Role of the microbiota in DNA methylation and CRC development

Award Number: R01CA214005

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/15/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2023

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer